Substituted benzimidazoles such as for instance the compounds with the generic names omeprazole, lansoprazole, pantoprazole, pariprazole and leminoprazole have properties making the compounds useful as inhibitors of gastric acid secretion. This class of compounds is known as proton pump inhibitors of H.sup.+ K.sup.+ ATPase inhibitors. There are a large number of patents and patent applications disclosing such proton pump inhibitors and processes for their preparation.
There is a general need in industry that pharmaceutically active compounds should be produced by processes giving products with properties making them suitable for pharmaceutical preparations, such as being easy to handle in a full scale production and having good storage stability.
WO 95/01977 discloses a novel magnesium salt of omeprazole with a specific degree of crystallinity making the product suitable for pharmaceutical formulations. The novel product is prepared by a process comprising the following steps; reacting omeprazole with magnesium alcoholate; separating inorganic salts from the reaction mixture; crystallizing the magnesium salt of omeprazole and isolating the product. The magnesium alcoholate is formed from metallic magnesium which requires special process conditions. The use of magnesium alcoholate in the process constitutes a potential difficulty with the formation of relatively insoluble magnesium salts, such as magnesium hydroxide. Filtration of such magnesium hydroxide is complicated because of gelling and extremely small particle size. The prior process is rather complicated, is water sensitive and requires special conditions. The prior process also has a large equipment requirement in the form of three reaction vessels and a separator. Therefore, there is a need for a more efficient process resulting in shorter manufacturing time, less reaction equipment and giving a higher yield pro volume.
The present invention provides improvements over the process disclosed in WO 95/01977 for the preparation of the magnesium salts of omeprazole and of other substituted benzimidazoles. Process for the preparation of certain salts of the single enantiomers of omeprazole, such as the magnesium salts, and processes for their preparation are described in EP 94917244.9.
As discussed in WO 95/01783 the magnesium salts of proton pump inhibitors, such as the magnesium salt of omeprazole, are especially suitable for the manufacturing of pharmaceutical formulations, such as tablets. The magnesium salts are stable, they may be easily purified by crystallization, and are easy to handle in pharmaceutical procedures and processes.